Stereoselective synthesis of tapentadol and its salts

Abstract

A process for the synthesis of a salt of tapentadol.

We claim: 
     
         1 . A process for synthesis of a salt of tapentadol, the process comprising:
 (a) reacting (E)-3-(3-hydroxyphenyl)acrylic acid in a suitable solvent with benzyl bromide to obtain (E)-3-(3-(benzyloxy)phenyl)acrylic acid   
       
         
           
           
               
               
           
         
         (b) reducing (E)-3-(3-(benzyloxy)phenyl)acrylic acid in a suitable solvent to obtain (E)-3-(3-(benzyloxy)phenyl)prop-2-en-1-ol 
       
       
         
           
           
               
               
           
         
         (c) reacting (E)-3-(3-(benzyloxy)phenyl)prop-2-en-1-ol with allyl bromide in a suitable solvent to obtain (E)-1-(3-(allyloxy)prop-1-enyl)-3-(benzyloxy)benzene 
       
       
         
           
           
               
               
           
         
         (d) isomerizing (E)-1-(3-(allyloxy)prop-1-enyl)-3-(benzyloxy)benzene with an organometallic catalyst in a suitable solvent to obtain 1-(benzyloxy)-3-((E)-3-((E)-prop-1-enyloxy)prop-1-enyl)benzene 
       
       
         
           
           
               
               
           
         
         (e) reacting 1-(benzyloxy)-3-((E)-3-((E)-prop-1-enyloxy)prop-1-enyl)benzene with 4-(dimethylamino)-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)picolinamide in the presence of a suitable organometallic catalyst to obtain (2R,3R)-3-(3-(benzyloxy)phenyl)-2-methylpent-4-enal 
       
       
         
           
           
               
               
           
         
         (f) reducing (2R,3R)-3-(3-(benzyloxy)phenyl)-2-methylpent-4-enal in a suitable solvent with a suitable reducing agent to obtain (2R,3R)-3-(3-(benzyloxy)phenyl)-N,N,2-trimethylpent-4-en-1-amine 
       
       
         
           
           
               
               
           
         
         (g) reacting (2R,3R)-3-(3-(benzyloxy)phenyl)-N,N,2-trimethylpent-4-en-1-amine with a suitable acid HX to obtain a salt of (2R,3R)-3-(3-(benzyloxy)phenyl)-N,N,2-trimethylpent-4-en-1-amine 
       
       
         
           
           
               
               
           
         
       
       and
 (h) hydrogenating the salt of (2R,3R)-3-(3-(benzyloxy)phenyl)-N,N,2-trimethylpent-4-en-1-amine to obtain the salt of tapentadol 
 
       
         
           
           
               
               
           
         
       
     
     
         2 . The process according to  claim 1 , wherein the suitable solvent of steps (a) to (g) are each organic solvents, preferably anhydrous organic solvents. 
     
     
         3 . The process according to  claim 1 , wherein the suitable solvent of step (a) is anhydrous dimethylformamide (DMF), anhydrous dimethylsulfoxide (DMSO), anhydrous dimethyl acetamide (DMAc), anhydrous ethanol, anhydrous methanol, anhydrous n-propanol, anhydrous 2-butanol, anhydrous 1-butanol, anhydrous tetrahydrofuran (THF), anhydrous 2-methyltetrahydrofuran (2-MeTHF), anhydrous dioxane, anhydrous toluene, anhydrous ethyl acetate, anhydrous isopropyl acetate, or a mixture thereof. 
     
     
         4 . The process according to  claim 1 , wherein the suitable solvent of step (b) is anhydrous 2-MeTHF, anhydrous THF, anhydrous toluene, anhydrous dioxane, anhydrous methyl tert-buyl ether (MTBE), anhydrous cyclopentyl methyl ether, or anhydrous diethyl ether. 
     
     
         5 . The process according to  claim 1 , wherein step (b) is accomplished using a suitable reducing agent, the reducing agent preferably selected from lithium borohydride, sodium borohydride, lithium aluminum hydride, disobutyl aluminum hydride, or RedAl. 
     
     
         6 . The process according to  claim 1 , wherein the suitable solvent of step (c) is THF, 2-MeTHF, toluene, dioxane, MTBE, cyclopentyl methyl ether, diethyl ether, or a mixture thereof. 
     
     
         7 . The process according to  claim 1 , wherein, the organometallic catalyst of step (d) is [Ir(COD)Cl] 2  or [Ir(COE) 2 Cl] 2 . 
     
     
         8 . The process according to  claim 1 , wherein the suitable solvent of step (d) is dichloromethane, THF, toluene, dioxane, MTBE, cyclopentyl methyl ether, diethyl ether, acetone, or a mixture thereof. 
     
     
         9 . The process according to  claim 1 , wherein the 4-(dimethylamino)-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)picolinamide is obtained by reacting 4-(dimethylamino)picolinic acid with (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol in a suitable solvent, preferably anhydrous DMF 
       
         
           
           
               
               
           
         
       
     
     
         10 . The process according to  claim 1 , wherein the organometallic catalyst of step (e) is [CpRu(MeCN) 3 ]PF 6  or [Cp*Ru(MeCN) 3 ]PF 6 . 
     
     
         11 . The process according to  claim 1 , wherein the suitable solvent of step (e) is anhydrous THF, anhydrous 2-MeTHF, anhydrous toluene, anhydrous dioxane, anhydrous MTBE, anhydrous cyclopentyl methyl ether, anhydrous diethyl ether, or a mixture thereof. 
     
     
         12 . The process according to  claim 1 , wherein the suitable solvent of step (f) is THF, 2-MeTHF, toluene, dioxane, MTBE, cyclopentyl methyl ether, diethyl ether, dichloromethane, dichloroethane, or a mixture thereof, preferably THF or 2-MeTHF. 
     
     
         13 . The process according to  claim 1 , wherein the suitable solvent of step (g) is MTBE, cyclopentyl methyl ether, diethyl ether, acetonitrile, or a mixture thereof. 
     
     
         14 . The process according to  claim 1 , the suitable acid HX of step (g) is hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, lactic acid, citric acid, glutaminic acid, acetylsalicylic acid, nicotinic acid, aminobenzoic acid, α-lipoic acid, hippuric acid, or aspartic acid, preferably hydrochloric acid. 
     
     
         15 . The process according to  claim 1 , wherein the salt of step (g) is obtained by seeding with crystals of the salt of (2R,3R)-3-(3-(benzyloxy)phenyl)-N,N,2-trimethylpent-4-en-1-amine. Such seeds were obtained the seeds by carefully running the desired crystallization to afford some crystalline solids and these solids were then used to crystallize the bulk material. 
     
     
         16 . The process according to  claim 1 , wherein the hydrogenation of step (h) is accomplished with a hydrogenation catalyst, preferably palladium catalyst on carbon. 
     
     
         17 . The process according to  claim 1 , wherein the salt of tapentadol is converted to tapentadol by reaction with a base. 
     
     
         18 . (2R,3R)-3-(3-(benzyloxy)phenyl)-N,N,2-trimethylpent-4-en-1-amine or a salt thereof. 
     
     
         19 . A salt of (2R,3R)-3-(3-(benzyloxy)phenyl)-N,N,2-trimethylpent-4-en-1-amine. 
     
     
         20 . The chloride salt of (2R, 3R)-3-(3-(benzyloxy)phenyl)-N,N,2-trimethylpent-4-en-1-amine. 
     
     
         21 . A process for synthesis of a salt of tapentadol, the process comprising reducing (2R,3R)-3-(3-(benzyloxy)phenyl)-2-methylpent-4-enal in a suitable solvent with a suitable reducing agent to directly obtain tapentadol 
       
         
           
           
               
               
           
         
       
     
     
         22 . The process according to  claim 21 , wherein the reduction is accomplished with a hydrogenation catalyst, preferably palladium catalyst on carbon. 
     
     
         23 . The process according to  claim 21 , wherein the suitable solvent is an organic solvent, preferably an anhydrous organic solvent.